Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disorder in which multiple susceptibility genes have been identified. The genes implicated in SLE fall into four categories: [1] antigen presentation, [2] immune complex clearance, [3] dysregulated antibody production, and [4] dysregulated T cell function. FcgammaR plays a dominant role in the uptake of immune complexes in SLE patients who are hypocomplementemic. These receptors are widely expressed on hematopoietic cells and mediate inflammatory responses to IgG and IgG-immune complexes in addition to acting as receptors for their clearance. Inflammatory responses include phagocytosis, antibody-dependent cell-mediated cytotoxicity, release of cytokines, and release of reactive oxygen intermediates. Regulation of FcgammaR responses depends upon the balance achieved by signals transduced by activating receptors and signals transduced by inhibitory receptors. Our preliminary data suggest that macrophage responses to immune complexes are highly dependent on maturational status and milieu. We hypothesize that FcgammaR polymorphisms associated with decreased binding result in impaired clearance of immune complexes, particularly in SLE patients with active disease and hypocomplementemia. These circulating immune complexes deposit in end organs and incite an inflammatory response. The precise nature of the response depends critically on the prior experience or exposures of the responding cells, maturational status, and milieu. This sensitivity to environmental cues is probably required by a system that mediates both uptake, in which an inflammatory response is undesirable, and response to infection, in which an inflammatory response is desirable. To investigate the role of FcgammaR in SLE, we will determine the role of FcgammaR polymorphisms in the susceptibility to SLE. In specific aim 2, we will define the signaling pathways important in the responses to immune complexes and transcription factors relevant for the response of the TNFalpha gene to immune complexes. In the third aim, we will define the role of chromatin in the regulation of responses to immune complexes.